What is the recommended treatment regimen for lupus nephritis using mycophenolate mofetil (MMF) and prednisone?

Treatment of Lupus Nephritis with Mycophenolate and Prednisone

For Class III or IV lupus nephritis, mycophenolate mofetil (MMF) 2-3 g/day combined with glucocorticoids is the recommended first-line treatment with the best efficacy/toxicity ratio. 1

Initial Treatment Regimen

Mycophenolate Dosing

• Target dose: 2-3 g/day of MMF (or mycophenolic acid at equivalent dose) for 6 months 1, 2
• For combination therapy with calcineurin inhibitors, a lower MMF dose of 1-2 g/day is used, particularly effective in patients with nephrotic-range proteinuria 1, 3

Glucocorticoid Protocol

• Start with intravenous methylprednisolone pulses: 500-2500 mg total dose (typically 500-750 mg for 3 consecutive days), depending on disease severity 1, 2
• Follow with oral prednisone 0.3-0.5 mg/kg/day for up to 4 weeks 1, 4
• Taper aggressively to ≤7.5 mg/day by 3-6 months 1, 2

This steroid-sparing approach minimizes cumulative glucocorticoid toxicity while maintaining efficacy. 1

Class-Specific Modifications

Class V (Pure Membranous) Nephritis

• MMF 2-3 g/day plus pulse IV methylprednisolone (500-2500 mg total), followed by oral prednisone 20 mg/day, tapered to ≤5 mg/day by 3 months 1
• This regimen is specifically recommended for nephrotic-range proteinuria or UPCR >1000 mg/g despite optimal renin-angiotensin-aldosterone system blockade 1

High-Risk Patients

For patients with reduced GFR, histological crescents, fibrinoid necrosis, or severe interstitial inflammation, the standard MMF/prednisone regimen remains appropriate, though high-dose cyclophosphamide can be considered as an alternative 1, 2

Essential Adjunctive Therapy

Hydroxychloroquine

• Mandatory co-administration at ≤5 mg/kg/day, adjusted for GFR 1, 2, 4
• Improves long-term outcomes by reducing renal flares and limiting cardiovascular damage 4

Renoprotective Agents

• ACE inhibitors or ARBs for all patients with UPCR >500 mg/g or hypertension 1, 4

Cardiovascular Protection

• Statins based on lipid levels and 10-year cardiovascular risk 1, 4

Bone Protection

• Calcium/vitamin D supplementation and/or antiresorptive agents given glucocorticoid exposure 1

Treatment Goals and Monitoring Timeline

Response Targets

• 25% reduction in proteinuria by 3 months 1, 2, 4
• 50% reduction in proteinuria by 6 months 1, 2, 4
• UPCR <500-700 mg/g by 12 months (complete clinical response) 1, 2

Important Caveat

Patients with baseline nephrotic-range proteinuria may require an additional 6-12 months to reach complete response; do not switch therapy prematurely if proteinuria is steadily improving 1

Monitoring Schedule

• Every 2-4 weeks for the first 2-4 months 4
• Track: serum creatinine, eGFR, proteinuria, urinary sediment, C3/C4, anti-dsDNA antibodies, complete blood count 4

Maintenance Therapy (After Initial Response)

Continue MMF at reduced dose of 1-2 g/day OR switch to azathioprine 2 mg/kg/day (preferred if pregnancy contemplated), combined with low-dose prednisone 2.5-5 mg/day 1, 4

• Maintain for at least 3-5 years in complete clinical response 1, 4
• MMF is superior to azathioprine in preventing treatment failure (death, ESRD, doubling of creatinine, renal flare) based on the largest international trial 1
• Hydroxychloroquine should be continued long-term 1

Management of Inadequate Response

If No Improvement by 3-4 Months or Partial Response Only by 6-12 Months:

1. First assess adherence and perform therapeutic drug monitoring 1, 4
2. Switch from MMF to cyclophosphamide (or vice versa if initially on cyclophosphamide) 1, 4
3. Add 3 days of IV methylprednisolone pulses with the switch 1
4. Consider rituximab 1000 mg on days 0 and 14 for refractory disease 1, 4
5. Consider adding calcineurin inhibitor (especially tacrolimus) for persistent nephrotic-range proteinuria, particularly in Class V 1, 4

Critical Pitfalls to Avoid

• Do not use MMF monotherapy—always combine with glucocorticoids initially 1
• Do not maintain high-dose prednisone beyond 4-6 weeks—aggressive tapering reduces toxicity without compromising efficacy 1
• Do not switch therapy prematurely—allow 6 months (or 12-18 months for nephrotic-range proteinuria) if proteinuria is improving 1
• Do not forget renal biopsy—histological class guides therapy selection 2, 4
• Do not omit hydroxychloroquine—it is essential for long-term outcomes 1, 4